PARPinhibit · A systems biology approach to tackle PARP-inhibitors resistance and identify novel therapeutic targets to overcome it
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2020-12-31 → 2023-12-30
- EU contribution
- €251,003
- Participants
- 2
- Scheme
- MSCA-IF
Lines connect the coordinator with its partners.
Results in brief
A systems biology approach to tackle PARP-inhibitors resistance and identify novel therapeutic targets to overcome it
The Poly(ADP-ribose) polymerase 1 (PARP1) gene encodes a nuclear protein that transfers ADP-ribose residues (PAR) onto target substrates; this post-translational modification is called PARylation. Inhibition of PARP1 is widely used in cancer therapy to treat cancers where DNA repair is defective, particularly through homologous recombination (HR), such as breast, prostate, pancreatic, and ovarian cancers caused by inactivation of BRCA1 or BRCA2; however, despite their demonstrated efficacy, development of resistance to PARP inhibitors (PARPi) is a wide diffuse problem and still little is known about how to tackle this significant challenge. Therefore, the overall objectives of the project are to identify targets that can be modulated as single agents or in the context of a combined approach to overcome development of PARPi resistance; we planned to do that by identification of genes whose inhibition influence PARylation activity and PARP1 retention to DNA and that also influence sensitivity to PARP inhibitors. We can conclude that we discovered and studied in depth an interesting novel target important for PARP1 activity, able to regulate its function and DNA binding in cells. Moreover, we evaluate how modulation of this gene influences sensitivity of ovarian cancer cells to treatment with PARPi, to DNA damage induced with ionizing radiation exposition and to a combination of both treatments. In conclusion, with further analysis, treatment of this target could become relevant in cancer therapy, particularly in those cancers where PARP inhibitors are currently administered such as ovarian cancer.
Data: CORDIS, © European Union
Project objective
Inhibition of PARP1 in cancer therapy is a recently adopted strategy to treat cancers where DNA repair is defective, such as breast and ovarian cancer caused by mutations in BRCA1 or BRCA2. In addition, PARP1 inhibitors (PARPi) can be useful even in the absence of BRCA mutations, likely due to pathogenic variants or epigenetic inactivation of other DNA repair related genes. However, development of resistance to PARPi is a significant challenge.To address this challenge, I propose to identify proteins that modulate PARP1 activity that could be used as additional therapeutic targets. The strength of this project is based on a systems biology overall strategy exploiting multiple independent datasets to identify candidates protein interactors, followed by a rigorous biochemical and genetic approach to characterize this interaction. Analysis of identified proteins and their role in PARPi resistance will be achieved at three main levels: a) in-silico and molecular studies of the interaction; b) influence on PARP1 activity and role in PARPi resistance after CRISPR-cas9 editing; c) expression levels in breast and ovarian cancer tissues. Results from this project will illuminate mechanisms of PARPi resistance and generate potential targets for therapy in breast and ovarian cancer. These results will contribute to the reduction in mortality due to breast and ovarian cancer and they will give an answer to this world-wide diffuse challenge.
Original text from CORDIS.
Participants
- CONSIGLIO NAZIONALE DELLE RICERCHE · RomaCoordinatorItaly
- H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE INC · TAMPA FLUnited States
Links
Data: CORDIS, © European Union